Human lipoprotein-associated phospholipase A2, also known in the art as Platelet Activating Factor Acetyl Hydrolase (PAF acetyl hydrolase), is one of a family of enzymes that catalyze release of fatty acids from membrane phospholipids and can thereby initiate synthesis of proinflammatory mediators. During the conversion of LDL to its oxidised form, lipoprotein-associated phospholipase A2 is responsible for hydrolysing the sn-2 ester of oxidatively modified phosphatidylcholine to give lyso-phosphatidylcholine and an oxidatively modified fatty acid. Both of these products of human lipoprotein-associated phospholipase A2 action are potent chemoattractants for circulating monocytes. The enzyme appears to play a central role in the development of atherosclerosis and is regarded as an independent risk factor for coronary artery disease (Caslake et al., Atherosclerosis 150: 413-19, 2000). Specifically, this enzyme is thought to be responsible for the accumulation of cells loaded with cholesterol ester in the arteries, causing the characteristic ‘fatty streak’ associated with the early stages of atherosclerosis. Recently, medicinal chemists have begun to design and prepare lipoprotein-associated phospholipase A2 inhibitors for use in preventing or inhibiting progression of atherosclerotic diseases (See, for example, U.S. Pat. Nos. 5,981,252 and 5,968,818; Boyd et al., Bioorg. Med. Chem. 10: 2557-61, 2000).
The level of PAF acetylhydrolase has been found to be altered in several disease states. For example, acquired deficiency of PAF acetylhydrolase activity has been reported in patients with systemic lupus erythematosus, stroke and asthma, and increased levels of PAF have been reported in children with acute asthmatic attacks (see, for example, Hiramoto et al., Stroke 28: 2417-2420, 1997; Kruse et al., Am. J. Hum. Genet. 66: 1522-1530, 2000; Stafforini et al., J. Clin. Invest. 97: 2784-2791, 1996). Miwa et al. (1988, J. Clin. Invest. 82:1983-1991) have also described an autosomal recessive form of PAF acetylhydrolase deficiency which has been observed only in the Japanese population. PAF acetylhydrolase activity was absent in 4% of the Japanese population. This inherited deficiency is the result of a point mutation in exon 9 and completely abolishes enzymatic activity. These patients suffer from severe asthma. Results from further studies indicated that the variant allele thr198 was found to be highly associated with total IgE concentrations in an atopic population and with ‘asthma’ in an asthmatic population (Kruse et al., 2000, Am. J. Hum. Genet. 66:1522-1530). The variant allele val379 was found to be highly associated with ‘specific sensitization’ in the atopic population and with ‘asthma’ in the asthmatic population.
The full length cDNA clone has been isolated (see U.S. Pat. Nos. 5,981,252 and 5,968,818) and the DNA sequence has been determined. The complete amino acid sequence has been deduced from the DNA sequence. A gene encoding the human lipoprotein-associated phospholipase A2 polypeptide is located at gene map locus 6p21.2-p12.